Phase 1 dose‐escalation trial evaluating the combination of the selective MET (mesenchymal‐epithelial transition factor) inhibitor tivantinib (ARQ 197) plus erlotinib

Abstract

BACKGROUND: Amplification of the mesenchymal‐epithelial transition factor (MET) gene can promote tumor resistance to epidermal growth factor receptor (EGFR) inhibition. Dual EGFR‐MET inhibition may overcome this resistance. Tivantinib (ARQ 197) is a selective, oral, non–ATP‐competitive, small‐molecule inhibitor of the MET receptor tyrosine kinase. This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of tivantinib combined with the EGFR inhibitor erlotinib. METHODS: Patients with advanced solid malignancies were administered oral tivantinib at escalating doses of 120, 240, 360, and 480 mg twice daily (BID) plus 150 mg erlotinib once daily (QD). Single or multiple intrapatient dose escalation was planned in the absence of dose‐limiting toxicity in the first cycle of therapy (21 days). RESULTS: Thirty‐two patients received combination treatment. Tivantinib serum concentrations were not dose‐proportional. The most common (≥20%) adverse events (AEs) regardless of causality included rash (n = 17), fatigue (n = 12), nausea (n = 10), abdominal pain (n = 10), diarrhea (n = 9), bradycardia (n = 9), and anemia (n = 7). AEs considered related to study treatment occurred in 28 patients (87.5%), and 5 patients (15.6%) had treatment‐related serious AEs, including neutropenia, leukopenia, syncope, sinus bradycardia, and sick sinus syndrome. Fifteen of 32 patients (46.8%) had a partial response (n = 1) or stable disease (n = 14) as assessed by Response Evaluation Criteria in Solid Tumors. Six of 8 patients with nonsmall cell lung cancer achieved stable disease. The recommended phase 2 dose is tivantinib 360 mg BID plus erlotinib 150 mg QD. CONCLUSIONS: Tivantinib plus erlotinib was well tolerated with encouraging clinical activity, especially in patients with nonsmall cell lung cancer. Cancer 2012. © 2012 American Cancer Society.

Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells

“…Several studies have demonstrated that in lung adenocarcinoma-derived cells the EGFR inhibition can be overcome by MET (19,22). Moreover, HGF-dependent MET activation also proved to be a mechanism of intrinsic resistance to gefitinib in NSCLC cells with EGFR-activating mutations and no MET gene amplification (22).…”

“…Moreover, HGF-dependent MET activation also proved to be a mechanism of intrinsic resistance to gefitinib in NSCLC cells with EGFR-activating mutations and no MET gene amplification (22). MET amplification is associated with acquired resistance to anti-EGFR treatment in patients with mCRC who have not selected a KRAS mutation during the therapy (14).…”

“…Several clinical studies have evaluated the combination of MET and EGFR inhibitors in patients with non-small cell lung cancer (NSCLC; refs. [21][22][23].…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…Interestingly, a number of phase I trials of HGF/cMET targeting agents have included patients with ovarian cancer, [82,97,88,54,98,61] …”

The Role of MET Receptor Tyrosine Kinase in Non-Small Cell Lung Cancer and Clinical Development of Targeted Anti-MET Agents

“…A phase I trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of tivantinib in combination with erlotinib in patients with advanced solid tumors, including eight patients with NSCLC. Fifteen of 32 patients (47%) with advanced solid tumors had a PR (n ϭ 1) or SD (n ϭ 14), and six of eight patients (75%) with NSCLC achieved SD [50]. A recently reported randomized, placebo-controlled, phase II trial investigated erlotinib plus tivantinib in 173 previously treated, EGFR TKI-na ¨ve patients [52].…”